Non-Fluoropolymer Barrier Materials For Containers

ABSTRACT

A container having a barrier layer is provided. The container may be of thermoplastic and the barrier may inhibit materials from leaching from the thermoplastic material or from extraction of compounds from medicants by the thermoplastic. A process is also described that allows for molding thin barrier layers as container lines and for forming thermoplastic containers with barrier liners.

FIELD

The present disclosure relates generally to non-lubricated syringes, and more specifically to non-fluorinated materials that are used to bond to an elastomeric body and a barrier materials.

BACKGROUND

Syringes used for delivery of medicaments are principally constructed of a barrel and a stopper. The stopper is slidably fitted within the syringe barrel and may have a stopper rod affixed to it for actuation of the syringe and delivery of medicament. The stopper is generally constructed of an elastomer, with silicone oil applied. The silicone oil is applied to reduce sliding friction between the stopper and barrel and to improve the seal between them. The oil allows for ease of sliding when administering a dose so that a full dose can be administered. Partial dosing is of particular concern in the case of pens and so-called auto injecting syringes. In such applications, the oil is also critical to prevent jamming of the device which can lead to trauma at the site of injection. The improved sealing provided by silicone oil also may ensure that no foreign contaminants like bacteria enter the syringe.

Recently there has developed a trend favoring pre-filled syringes which function to both store and deliver medicaments. Such pre-filled syringes may offer cost savings to the pharmaceutical industry and may improve safety, convenience and efficacy of medicament delivery. Biopharmaceuticals are an important class of pharmaceuticals that may increase the use of pre-filled syringes and related devices (pens, auto injectors and the like). Such biopharmaceuticals may include insulin, vaccines, antibodies, blood products, hormones, cytokines, and the like. As more pharmaceuticals and particularly biopharmaceuticals utilize delivery in pre-filled syringe and similar devices, the challenges of conventional syringe technology become apparent.

Several aspects of traditional syringe construction present a challenge for their use as pre-filled syringes. The use of silicone oil is a concern, because the oil may degrade the medicament and because a small amount of silicone may be injected with it. The oil may also be of particular concern with regard to biopharmaceuticals because it may cause aggregation of certain proteins.

Another issue that arises in prefilled syringes is that the elastomer of the stopper may contain leachable and extractable contaminants. These may also contaminate the medicament upon long term storage in syringes. Trace amounts of residual monomer or plasticizer or other impurities from the stopper can adversely effect the therapeutic or can have an adverse impact on the patient once injected.

Among the many other considerations affecting prefilled syringe devices and similar devices and their components are the need to be sterilized, stability with transport and storage for up to a few years, optical clarity, the need to integrate into existing filling equipment (including the durability requirements for stopper cleaning and insertion into the syringe barrel), leachables and extractables of all components of the syringe, and the need to maintain sterility from filling through administering of the contents, and finally user preferences and ergonomic considerations. For a variety of reasons the prefilled syringe market uses both glass and plastic barrels.

The foregoing considerations apply in similar manner to other containers, particularly containers suitable for medicaments. For example, rigid tip caps and other container closures as well as syringe barrels may benefit from barrier materials. In some such applications, the improved barrier material may serve as a barrier between the product contained in the container and the environment.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are included to provide a further understanding of the disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments, and together with the description serve to explain the principles of the disclosure.

FIG. 1 is a schematic illustration of the thermoforming equipment used to make barrier film preforms in accordance with one embodiment of the invention;

FIG. 2 depicts a 4-cavity mold a used with thermoforming equipment in accordance with one embodiment of the invention;

FIG. 3 is a schematic illustration of the lay-up in the press for compression molding in accordance with one embodiment;

FIG. 4 is a schematic illustration of the cavity used to make the stopper in Example 7 in accordance with one embodiment;

FIG. 5 is a schematic illustration of a cross sectional view of a syringe stopper according to one embodiment;

FIG. 6 is a schematic illustration of a cross sectional view of a syringe stopper according to another embodiment;

FIG. 7 is a schematic illustration of a cross sectional view of a syringe stopper according to another embodiment;

FIG. 8 is a schematic illustration of a cross-sectional view of a syringe stopper in accordance with yet another embodiment;

FIG. 9 is a schematic illustration of a cross-sectional view of a syringe stopper according to another embodiment;

FIG. 10 is a schematic illustration of a cross-sectional view of a syringe stopper in accordance with one embodiment;

FIG. 11 is a schematic illustration of a cross-sectional view of a syringe stopper in accordance with one embodiment;

FIG. 12 is a schematic illustration of a cross-sectional view of a syringe stopper in accordance with one embodiment;

FIG. 13 is a schematic illustration of cross-sectional view of a syringe stopper in accordance with one embodiment;

FIG. 14 is a schematic illustration of a test apparatus for accessing the barrier properties of a stopper in accordance with one embodiment;

FIG. 15 is a schematic illustration of a test apparatus to determine the durability of a stopper to the vent tube installation test in accordance with one embodiment;

FIG. 16 is a scanning electron micrograph (SEM) of the cross-section taken at 2000× magnification in accordance with one embodiment;

FIGS. 17 a and 17 b are schematic illustrations of a container in accordance with other embodiments; and

FIGS. 18 a and 18 b illustrate a cross sectional view and a top view, respectively, of a vial stopper having a barrier layer in accordance with other embodiments.

DESCRIPTION OF THE INVENTION

Persons skilled in the art will readily appreciate that various aspects of the present disclosure can be realized by any number of methods and apparatus configured to perform the intended functions. It should also be noted that the accompanying drawings referred to herein are not necessarily drawn to scale, but may be exaggerated to illustrate various aspects of the present disclosure, and in that regard, the drawing should not be construed as limiting. It is to be appreciated that the terms “film” and “membrane” may be used interchangeably herein.

The present disclosure provides a syringe stopper that is suitable for use in syringes without silicone oil or other liquid lubricants. In one aspect, a low friction barrier material is provided between an elastomeric stopper material and a therapeutic in the syringe. The barrier may inhibit materials from leaching from the elastomer material or materials obtained from the extraction of compounds from medicants by the elastomer. A process is also described that allows for molding thin barrier layers while allowing adequate bonding with the elastomer.

In another aspect, the barrier material may also be used on non-elastomeric materials such as, but not limited to plastics (e.g., polypropylene, polycarbonate, and polyethylene) thermoplastics, and fluoropolymer materials such ethylene-(perfluoro-ethylene-propene) copolymer (EFEP), polyvinylidene difluoride (PVDF), and perfluoroalkoxy polymer resin (PFA).

In certain embodiments, the barrier films including expanded fluoropolymer films and, particularly expanded polytetrafluoroethylene films, may be used. Barrier films based on expanded fluoropolymers (e.g., expanded polytetrafluoroethylene (ePTFE)) can provide for thin and strong barrier layers to both leachables and extractables. The superior strength of the expanded fluoropolymer structure allows these materials to form thin barriers which remain intact during the forming process and installation of the stopper into the syringe body.

The use of at least partially porous and advantageously fibrilizing materials, such as ePTFE, in combination with barrier materials provide many advantages. In one aspect, the use of such partially porous materials may provide a scaffold that enables thin strong barrier layers to be made and improves the bond between the elastomer and the barrier. Barrier compliance is critical to maintaining a seal between the stopper and the barrel; porous materials may also provide for improved compliance of the stopper. Improved compliance may result from reduced film thickness, flexural compliance, or the compressibility of one or more layers of the porous material. Accordingly, by providing a barrier that is at least partially porous to the outside of the syringe stopper, the seal between the stopper and syringe barrel may be improved while the sliding force is minimized.

The barrier may have a single layer or multiple layer construction. As described herein, layers may be described functionally. However, the functional names of the various layers in the descriptions of embodiments that follow may not describe all of the potential functions of any given layer. Accordingly, it will be understood that such functional nomenclature is not intended to be limiting of any layer property. For example, a barrier layer may have additional properties and functions such as providing a low friction surface and/or increasing bond strength. Additionally, in multi-layer embodiments, each layer may contribute to the reduction of leachable and extractable materials regardless of its designation as a barrier layer or otherwise.

FIG. 5 shows a first embodiment of syringe stopper that includes an elastomer body 10 and a barrier 20. The elastomer body 10 can be formed of, or include, any elastomer suitable for the application, most notably rubbers constructed with butyl, bromobutyl, chlorobutyl, silicone, nitrile, styrene butadiene, polychloroprene, ethylene propylene diene, fluoroelastomers, or blends of any of the foregoing. The material(s) of the barrier 20 are chosen to provide a low coefficient of friction, compliance, low extractables and leachables, and good barrier properties, particularly as they relate to extractables and leachables from the elastomer body.

In one embodiment, the barrier 20 may be formed of a single layer. FIG. 8 schematically depicts a portion of a syringe stopper that is formed of an elastomer body 10 and a barrier layer 30. The elastomer body 10 may be formed of or include, any of the previously mentioned materials. In at least one embodiment, the barrier layer 30 may be formed of a densified expanded fluoropolymer, such as, for example, densified expanded polytetrafluoroethylene (ePTFE) film.

A densified ePTFE film may be obtained in the manner described in U.S. Pat. No. 7,521,010 to Kennedy, et al. The densified ePTFE film may be combined with an elastomer to construct a syringe stopper, such as is depicted in FIG. 8. In this embodiment, the densified ePTFE film is thermoformed to make a preform. Thermoforming is done at process temperatures sufficiently above the nodal melt temperature to ensure melt forming while preserving barrier and strength properties. The high strength expanded ePTFE film allows for forming extremely thin barrier films. Barrier films can be made with thicknesses ranging from 0.5 micron to 20 microns. The films are preferentially less than 30 microns. Additionally, the films can optionally be pre-treated or post-treated with chemical etching, plasma treating, corona, roughening or the like to improve bonding to the elastomer body.

The thermoformed, densified ePTFE preform can be combined with the elastomer body by injection molding, compression molding, priming and post laminating around an elastomer perform, or any other suitable means. Examples of elastomers that can be used to form the elastomer body include, but are not limited to, silicone, butyl, nitrile, polyurethane, fluoroelastomers, styrene ethylene butadiene styrene elastomers, and styrene butadiene rubbers.

In another embodiment, the barrier 20 may be formed of a composite fluoropolymer or non-fluoropolymer material having a barrier layer 30 and a tie layer 40. It is to be noted that, as used herein, the term “tie layer” may include fluoropolymer and/or non-fluoropolymer materials. The barrier layer 30 can include or be formed of, densified expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), densified polytetrafluoroethylene (PTFE), expanded modified PTFE, expanded copolymers of PTFE, fluorinated ethylene propylene (FEP), perfluoroalkoxy copolymer resin (PFA), polyethylene, polypropylene, polyvinylidene fluoride, polyvinylfluoride, perfluoropropylevinylether, and perfluoroalkoxy polymers. Patents have been granted on expandable blends of PTFE, expandable modified PTFE, and expanded copolymers of PTFE, such as, but not limited to, U.S. Pat. No. 5,708,044 to Branca; U.S. Pat. No. 6,541,589 to Baillie; U.S. Pat. No. 7,531,611 to Sabol et al.; U.S. Pat. No. 8,637,144 to Ford; and U.S. patent application Ser. No. 12/410,050 to Xu et al.

The tie layer 40 can include, or be formed of, ePTFE or other porous expanded and advantageously fibrilizing fluoropolymers (for example, ePTFE as taught in U.S. Pat. No. 6,541,589). Alternatively, the tie layer 40 may be formed of, or include, non-fluoropolymer materials. Non-limiting examples of suitable non-fluoropolymer materials for use in or as the tie layer 40 include non-fluoropolymer membranes, non-fluoropolymer microporous membranes, non-woven materials (e.g., spunbonded, melt blown fibrous materials, electrospun nanofibers), polyvinylidene difluoride (PVDF), nanofibers, polysulfones, polyethersulfones, polyarlysolfones, polyether ether ketone (PEEK), polyethylenes, polypropylenes, and polyimides. The microporous membranes may have a porosity from about 5% to about 95% and a pore size from about 1 nm to about 1 mm. Additionally, the tie layer 40 may be filled with an organic or inorganic material to provide color, lubricity, or other desired function.

In one or more embodiment, the barrier layer 30 and/or the tie layer 40 may include, or be formed of, one or more of the following materials: ultra-high molecular weight polyethylene as taught in U.S. Patent Publication No. 2014/0212612 to Sbriglia; polyparaxylylene as taught in U.S. patent application Ser. No. 14/810,999 to Sbriglia; polylactic acid as taught in U.S. patent application Ser. No. 14/811,054 to Sbriglia, et al.; and/or VDF-co-(TFE or TrFE) polymers as taught in U.S. patent application Ser. No. 14/811,100 to Sbriglia.

In another embodiment, a barrier 20 may be constructed by coating or otherwise depositing a barrier polymer onto the tie layer 40 to create a composite film. One such example is to deposit granular or powdered fluoropolymers such as powdered PTFE, or non-fluoropolymer materials onto the surface of the tie layer 40 in a coating process. The tie layer 40 should be constructed to be thermally stable enough to allow heat treatment of the deposited fluoropolymer or non-fluoropolymer material for the creation of a barrier 20 or for bonding of the deposited layer to the tie layer 40.

In certain embodiments, the elastomer material may advantageously penetrate the porous structure of the barrier. FIG. 6 shows a cross-section of a portion of a stopper according to an embodiment depicting the syringe barrel wall 50, the barrier layer 30, the tie layer 40, and the elastomer body 10. As shown in FIG. 6, there is a region of partial penetration 45 of the elastomer material into the tie layer 40. Penetration of the elastomer material into the tie layer 40 may improve the bond between the elastomer and the barrier layer 30.

FIG. 7 shows a cross-section of another embodiment of a portion of a stopper that includes the syringe barrel wall 50, a barrier 20 and an elastomer body 10. The barrier 20 is formed of a barrier layer 30 and a tie layer 40. In an exemplary embodiment, the barrier layer 30 includes a coating deposited onto the tie layer 40. In addition, the barrier layer 30 may include a polymer at least partially imbibed therein, such as from the tie layer 40, in a manner that creates a tie layer composite section 99. The tie layer composite section 99 may improve bonding of the barrier polymer to the tie layer. The tie layer composite section 99 may also provide support for the barrier polymer to impart strength, toughness, compliance, and stability, which may be beneficial in both the forming process and in the application.

In another aspect, the barrier layer 30 may include an imbibed barrier polymer applied in a manner that allows certain sections of the tie layer 40 exposed on the surface. In such an embodiment, the tie layer 40 may be sufficiently exposed to allow the exposed sections to come in contact with the syringe wall 50. In one embodiment, the porous polymer is advantageously formed of, or includes, ePTFE or another suitable lubricious, expanded porous fluoropolymer. The exposed sections of fluoropolymer may reduce the coefficient of friction of the barrier film against the wall.

In many of the embodiments of the invention, a tie layer 40 is disposed between the barrier layer 30 and the elastomer 10 of the stopper. The stopper may advantageously include various degrees of penetration of either the elastomer material or the polymer(s) forming the barrier layer into the material(s) forming the tie layer, such as is depicted generally in FIGS. 9 through 13. FIG. 9 is a cross-sectional view of a stopper showing the elastomer layer 10 and a barrier 20 including a fluoropolymer barrier layer 30 and a porous non-fluoropolymer or fluoropolymer tie layer 40. In the embodiment depicted in FIG. 9, the elastomeric material 10 substantially fills the pores of the tie layer 40.

In another embodiment, the polymer(s) of the barrier layer 30 may substantially fill the tie layer 40, as depicted in FIG. 10. In another embodiment, the tie layer 40 is filled to a substantially similar degree with barrier polymer 30 and elastomer 10, leaving few open pores in the porous structure. In still another embodiment, both the polymer(s) of the barrier layer 30 and the elastomer 10 partially fill the tie layer 40, while leaving some open pores between them, as depicted in FIG. 11. Other variations of the penetration of the elastomer and/or the polymer(s) of the barrier layer may be readily apparent. Some such embodiments are depicted in FIGS. 12 and 13. The various embodiments described herein may have advantages according to the specific application, with due consideration to the various desirable characteristics of the finished device, such as reduced friction, improved barrier properties, and/or improved sealing. The degree of penetration of either the polymer of the barrier layer or elastomer may be controlled by any known methods, but include variations in time, temperature, pressure, and porosity of the porous material. In one aspect the tie layer may, for example have a porosity that varies with depth.

In still another embodiment, the barrier layer 30 may include a composite of a densified ePTFE film and a thin layer of porous ePTFE bonded to the barrier layer film. A densified ePTFE film may be obtained as described in U.S. Pat. No. 7,521,010 to Kennedy et al. The ePTFE/densified ePTFE composite may be combined in the manner described in U.S. Pat. No. 6,030,694 to Dolan, et al.

In this embodiment, the composite barrier includes a layer of densified ePTFE film and a non-fluoropolymer or fluoropolymer tie layer. The tie layer is constructed in a manner that it retains most of its porosity through thermoforming. It is also sufficiently compliant in that it improves sealability against the syringe barrel wall. To accomplish this, at least a portion of the tie layer may remain sufficiently open after thermoforming and post compression molding with the elastomer. This open porosity allows some compressibility which may aid in the conformability and seal of the stopper to the surface.

The thickness of the densified ePTFE film would be suitably tailored to the application with pre-thermoform thicknesses of less than 100 microns, less than 50 microns, or less than 30 microns. Additionally, the flexural rigidity of the composite film would be suitably tailored to ensure compliance and sealability while retaining sufficient strength for the intended application.

The thickness of the tie layer may be less than 150 microns. To improve performance as a bonding layer, the tie layer should be made sufficiently open to allow for at least partial penetration of the elastomer into the tie layer during elastomer forming.

To construct a barrier preform, the composite barrier may be thermoformed at temperatures, rates, and pressures suitable to allow the barrier material to form to the shape of the female cavity of a stopper mold. The tie layer may be oriented toward the inside of the mold cavity, while the barrier layer may be oriented toward the outer wall of the mold. The thermoforming can be conducted at temperature ranges suitable to form the composite barrier 20 without fracturing or otherwise disturbing the barrier layer. Suitable temperatures range from 330 to 400° C. or 350 to 380° C. The thermoforming occurs at pressures suitable to form without fracturing the barrier layer or substantially collapsing the tie layer.

The thermoformed barrier preform may be integrated with an elastomeric syringe stopper as described herein by, for example, injection molding or compression molding an elastomer like butyl rubber or silicone or Viton® (e.g., synthetic rubber and fluoropolymer elastomer). The tie layer can be advantageously made stable to the elastomer injection or compression molding process, thereby maintaining some of its porous structure. The porous structure may improve the bond of the elastomer to the barrier, which may result in improved compliance for sealability, as the tie layer allows for some compressibility for better, low force sealing.

In yet another embodiment, a barrier can be made by forming a thin densified composite that includes a porous ePTFE layer and a thermoplastic barrier layer. In this aspect, a thermoplastic having a surface with a low coefficient of friction is preferred. Accordingly, fluoropolymer based thermoplastics such fluorinated ethylene propylene (FEP), a perfluoroalkoxy copolymer resin (PFA), or tetrafluoroethylene-hexafluoropropylene-vinylidene fluoride (THV) may be applicable. A barrier according to this aspect may be an FEP/ePTFE laminate obtained by following the process taught in WO 94/13469 to Bacino. The barrier may be formed at process temperatures above the softening temperature or even above the melt of the FEP film in a female cavity mold.

The composite barrier of ePTFE and FEP described above may allow the formation of surprisingly thin, strong barrier films. In one embodiment, the ePTFE layer may act as a support during shape forming to allow the formation of thin barrier films. The porous ePTFE layer may also act as a reinforcement to the thermoplastic layer to maintain film strength and integrity of the barrier layer. As described above, the ePTFE tie layer can also serve as a bonding layer when a portion of the ePTFE is allowed to remain porous and oriented toward the inside of the mold.

Subsequent combination of a composite film with an elastomer through, for example, compression molding can allow the porous portion of the ePTFE to be adhered by partial penetration of the elastomer into the porous structure. Alternatively, if the ePTFE/FEP composite barrier is fully imbibed in a manner that leaves no residual porosity in the composite film, the composite barrier film can be chemically modified by etching or plasma or physically modified by roughening, for example, to allow bonding to the elastomer. In another aspect, the ePTFE tie layer can be formed of, or include, multiple layers of ePTFE, each having varying pore size and structure. This multi-layer construction may facilitate the control of the degree of imbibing of the barrier polymer or the elastomer, or to allow other desired properties.

One surprising element of some embodiments is that the porous film portion of the expanded fluoropolymer layer can maintain its structure through thermoforming and post injection or compression molding of the elastomer. This allows for some of the advantages described above, including improved compliance and sealability, as well as an improved bond between the barrier film and the elastomer body.

In another embodiment, a composite barrier may be made by laminating an ePTFE tie layer to a densified ePTFE barrier layer using a thin layer of an adhesive, such as, for example, a fluoropolymer thermoplastic like PFA. In this embodiment, a syringe stopper can be made by combining the composite barrier with an elastomer layer such that the thermoplastic bonds the densified ePTFE barrier layer and the porous ePTFE layer. The ePTFE tie layer of the composite barrier is bonded to the elastomer (i.e. stopper) material during the molding process.

A composite film may be made by starting with a multilayer, porous expanded fluoropolymer film and substantially densifying one or more of the fluoropolymer or non-fluoropolymer tie layers. In one embodiment, the tie layer may be densified by application of pressure during the molding or syringe insertion process.

In another embodiment, a porous expanded fluoropolymer film could be formed, then post applied to create a barrier layer, such as, for example, by choosing an ePTFE film of suitable deformation characteristics such that it allows for deformation into the mold at relatively low temperatures (e.g., less than 200° C.). Such a suitable ePTFE film might, for instance, have tensile properties demonstrating high elongation or low modulus at the deformation temperature. The ePTFE film can be formed into the female mold cavity through a variety of methods including through the use of air pressure, through the use of a male mold form, or other suitable means to allow the formation of the ePTFE. One exemplary method would be to form an ePTFE film during the injection or compression molding process. This would allow for a structure where the ePTFE forms the outermost layer of the syringe stopper. The pore structure, thickness, and other properties can be suitably tailored to allow controlled penetration of the elastomer into the expanded fluoropolymer or non-fluoropolymer layer. In one embodiment, the elastomer is allowed to penetrate through the expanded fluoropolymer film, allowing for a composite structure of expanded fluoropolymer film and elastomer at the outer surface. If the outer surface is suitably dense and nodal, it can allow for a significant reduction of friction relative to the elastomer itself. One exemplary embodiment utilizes a stopper created using the aforementioned process of forming an ePTFE film in a female mold, then post laminating, imbibing or coating a barrier onto the ePTFE's outermost surface. In the coating and imbibing processes, the ePTFE film can be used to control the barrier thickness.

A syringe stopper of the current embodiment may be formed of a composite barrier that includes multiple tie layers, multiple barrier layers, or both. The properties of a composite barrier so constructed can be more suitably tailored to allow optimal compliance through the properties of the thin films while providing low surface friction against the barrel and adequate barrier properties to leachables, extractables, and gas permeation.

Another method of making an ePTFE syringe stopper with a porous outer layer and a barrier layer would be to post densify the ePTFE with pressure and temperature.

It will be appreciated that there are many variations of the processes described herein and such variations could be utilized without departing from the scope of the invention. Some of these variations may include, but are not limited to, the following:

Any of the ePTFE fluoropolymers used in syringe stopper of the current invention could be made with an expanded fluoropolymer film based on PTFE, modified PTFE, and PTFE and TFE copolymers such as, for example, the resins as described in U.S. Pat. No. 6,541,589 and US Patent Publication No. 2009/0093602.

There are also a wide variety of processes for forming the film and attaching it to the elastomer body which may be utilized without departing from the invention. In addition to what is described above, one could form an ePTFE film at low temperatures.

In another aspect, the disclosure provides an improved tip cap for a syringe. A tip cap may be provided as a protective covering to a syringe needle. Accordingly, a tip cap may provide a seal to the end of the needle to prevent contamination of a medicament. As with a syringe stopper, a tip cap construction that minimizes leachable and extractable components is desirable. Moreover, the tip cap must be readily removable. Moderate friction between the tip cap and needle is preferred. The tip cap may be of construction similar to that of the syringe stopper. In contrast to the stopper, however, the barrier layer is positioned in the tip cap to be adjacent to the needle on final assembly. As the challenges between tip cap and stopper are similar, each of the constructions described herein with regard to stoppers may also be adapted for use in a tip cap construction.

In another aspect, the invention provides an internal barrier layer for a container. The container may be formed of a material without barrier properties. The addition of a barrier layer to the inside surface of a container may improve barrier properties of the container. The container may be made of any material, including for example, a thermoset material, a thermoplastic material, metal, ceramic, or glass.

The container may be formed of a variety of materials. Advantageously, the material for the container is selected from materials that will form a bond with the barrier layer. In one aspect, the container is advantageously formed from a thermoplastic material. The container constructed of a thermoplastic material may be formed separately or simultaneously with the barrier layer. The barrier layer may be pre-formed to a shape approximating the inside of the container. The container and the preform may be placed together into a mold and formed under appropriate heat and pressure to the final shape of the container with barrier layer. In such an embodiment, the barrier layer may form a strong bond with the thermoplastic of the container during the final molding process.

In another aspect, the container may be a thermoset plastic material. Thermoset plastics may be injected into the mold at the time of final molding of the barrier or barrier composite preform. In another aspect, the thermoset plastic may be formed or made by other methods separately from the preform. In such an embodiment, the container of the thermoset plastic may function as the mold, and the barrier layer or composite barrier layer maybe molded to the thermoset material.

During the molding process, additional layers may be added to the barrier layer or composite barrier layer to construct a container or to improve bonding of a barrier or a barrier composite to the container. For example thermoplastic layers may be added to improve bonding to a thermoplastic container. In one embodiment, a PVDF layer (e.g., sheet) may be added to the molding process. The PVDF layer may add some rigidity to a thermoplastic container. In some embodiments, a relatively thick thermoplastic film may be formed in the mold to make the container. In another embodiment, a porous ePTFE film may be added between the thermoplastic layers to improve bonding between them.

The barriers and composite barriers of the present invention have shapes that are uniquely high aspect. Various measures are known in the art which reflect the aspect of the molded part. Included among these are several common expressions of draw ratio, including areal draw ratio, linear draw ratio, and height to diameter ratio.

Each of these measures is understood to reflect the work put into a thermoplastic during the molding process of simple shapes. From such measures the relative difficulty of maintaining barrier integrity in the molding process can be inferred. While such measures are useful, they do have limits in their ability to characterize complex shapes and to completely account for the thinning and breakdown of the barrier properties of when molding such shapes.

In order to better account for complex molded shapes, the shape factor may be used. As used herein, the shape factor is a ratio of the major diameter of the edge of a barrier to the maximum length of a cross section perimeter of the barrier. The edge of the barrier is defined as the intersection of an interior surface of the barrier and an exterior surface of the barrier. For example, for a syringe stopper, the barrier may be of generally convex shape. The interior surface of the barrier is oriented towards the glass syringe barrel and the exterior surface oriented towards the elastomeric material of the stopper. The barrier edge is the circular region at the intersection of the interior and exterior surface. The major diameter of the exemplary syringe is therefore the diameter of a circle defined by the barrier at the end of the stopper. The major diameter may also be understood to account for irregularly shaped barriers. The major diameter is considered the diameter the largest circle generally in plane with the barrier edge that would contact some point on the edge. The maximum cross section length is the longest length of the barrier perimeter in a cross section of the barrier made perpendicular to the major diameter.

In some constructions the shape factor may be conveniently determined with regard to measurements of the mold itself. In simple cylindrical shaped male and female molds for example, the major diameter may be approximated by the mold diameter, and the maximum cross section perimeter length be calculated from the mold dimensions.

In other embodiments, the molded barrier may be of more complex shape. For example, a molded barrier may have a generally low aspect when the entire barrier is considered, but include features which are of high shape factor within the barrier or mold. In such embodiments, the maximum shape factor is best calculated with reference to the specific features having shape factors. In such cases, the major diameter may be considered to be the major diameter of the feature and the cross section length determined with reference to the feature and not the entirety of the molded barrier. For example, with reference to FIG. 18, the molded barrier 801 used in connection with a vial stopper 803. The vial stopper has a insertion plug portion 804 and a flange portion 802. In this example, the major diameter of the barrier may be determined with reference to the insertion plug portion of the stopper rather than the larger diameter of the flange portion. The major diameter of the insertion plug portion may be measured at the intersection 815 of the insertion plug portion and the flange portion. Similarly, the maximum cross section length may ignore the flange of the stopper. With reference to FIG. 18, the maximum cross section is calculated as the sum of the perimeter length of each side 805 a and 805 b of the plug and the perimeter length of the end of the plug 807. The perimeter length of flange portion 802 is not included in the calculation. In this manner, the forming challenge may be most properly considered by the shape factor. The shape factor for several examples is tabulated below:

TABLE 1 Sample Example 9 Example 2 Example 10 Example 11 Major Diameter 7.84 8.76 12.7 15.9 (mm) Cross Section 36.49 16.56 63.5 47.7 Length (mm) Shape Factor 4.7 1.9 5.0 3.0

Persons skilled in the art will readily appreciate that various aspects of the present disclosure can be realized by any number of methods and apparatus configured to perform the intended functions. It should also be noted that the accompanying figures, referred to herein are not necessarily drawn to scale, but may be exaggerated to illustrate various aspects of the present disclosure, and in that regard, the figures should not be construed as limiting.

Test Methods

It should be understood that although certain methods and equipment are described below, other methods or equipment determined suitable by one of ordinary skill in the art may be alternatively utilized.

Breaking and Sliding Friction Test

The following procedure was used to evaluate the static and dynamic friction of embodiments of the invention. Each test syringe was attached to a variable pressure pump (Barnant Air Cadet—model 420-3901) by securing a ¼″ OD, ⅛″ ID silicone tube to its tip (the tip was not fitted with a needle). The stopper assembly with the barrier film was positioned in the syringe to be at the bottom of its motion (closest to the tip). At the beginning of each test, the pressure was slowly adjusted starting at 2 psi and increasing about 1 psi every 30 seconds until syringe stopper movement was initiated (away from tip). The pressure to initiate movement was noted as P break. After the movement was initiated, the pressure was reduced to the lowest level that still allowed sliding. This pressure was noted as P sliding. All pressures were recorded in PSI. The test provided relative data on sliding properties.

Air Leak Test

The same apparatus and setup as described above was then used to evaluate air leakage. The syringe stopper was attached to the pressure pump. However, in this test the stopper was moved to the topmost position within the syringe (farthest from the tip) and the syringe assembly was placed in a 2 Liter glass beaker filled with deionized water. The pressure was set to 3 psi. If no leaks were detected (any sign of visual bubble formation) after 5 minutes, the pressure was increased by 1 psi. This procedure was repeated on each syringe until leaking occurred (or about 15-17 psi when the air was sufficient to eject the syringe stopper from the barrel). The minimum pressure required to cause an observable leak after 5 minutes was recorded in psi. This test was used for evaluating air leakage on Examples 1A, 1B, 1C.

For Examples 1-8 and the comparative example, air leakage was evaluated by performing the test as specified by I.S. EN ISO 7886-1:1998 Annex B, with the following exceptions: i) A bourdon tube gauge was used in place of a manometer, and ii) Deionized water in place of freshly boiled water.

Static and Dynamic Force Test

The test was performed as specified by I.S. EN ISO 7886-1:1998 Annex G, with the following exceptions: i) Syringe is mounted so that nozzle is pointing down, ii) No liquid was expelled; only air was expelled, and iii) Forces resulting form travel from the total graduated capacity position to 20 mm from that point were recorded.

Static force is defined as the value at the first inflection point in the force versus displacement graph. Dynamic force is the value after 15 mm of travel.

Toluene Exposure Test

This test was used to assess the barrier properties of stoppers. A schematic illustration of the test apparatus is shown in FIG. 14. The initial weight of the stopper was measured using a balance. The stopper (160) was loaded into the barrel (162) of a glass syringe. 1 ml of Toluene (166) was introduced into the barrel through the luer port (164). The luer port was sealed using a tip cap. The entire apparatus was left under the lab hood for 5 hours at room temperature. After 5 hours, the Toluene was removed from the barrel using a syringe. The stopper was removed from the barrel using compressed air. Upon removal of the stopper, it was quickly dried using a Kimwipe® and immediately weighed using the balance. Lower the weight gain of the stopper compared to its initial weight, the more effective its function as a barrier. Less than 1 mg weight gain of the stopper may indicate an effective barrier.

Vent Tube Installation Procedure

FIG. 15 describes a schematic of the test apparatus comprising a vent tube (170) meant for a 1 mL standard stopper (as specified in ISO11040-5) and a plunger (172). The vent tube, part of a SVH200 Semiautomatic Stoppering Machine from Groninger was used in this procedure. The apparatus was loaded into a universal testing machine capable of moving the plunger at a rate of 0.7 meters/sec. As shown in FIG. 15, the stopper (174) was placed on to the top of the vent tube (170). The test was initiated by moving the plunger at a rate of 0.7 meters/sec to push the stopper through the vent tube. The test was complete when the stopper traversed the entire length of the vent tube.

Tensile, Modulus, Strain to Break

Materials were evaluated for tensile strength, modulus and strain to break according to ATM D882-10 using 0.25 inch by 3 inch samples and a cross head rate of 20 inches/min and one inch gauge length.

EXAMPLES Example 1A, 1B and 1C

Examples of certain embodiments of the invention were constructed using a single layer of densified ePTFE films as the barrier. The films were obtained by process described in U.S. Pat. No. 7,521,010 to Kennedy, et al. The films had thicknesses of 25 microns, 10 microns, and 5 microns, respectively. Eight commonly available disposable plastic syringe barrels and stoppers with shafts were obtained. Four were 1 ml plastic syringes and four were 3 ml plastic syringes. Each included an elastomer stopper comprising a butyl rubber. The syringes were thoroughly washed with 95% hexane to remove any silicone oil. The washed syringe barrels and stoppers were allowed to dry for 5 days on an airhood to ensure complete evaporation of the hexane. Syringe stoppers were made by taking a densified ePTFE film and applying it to the stopper. Samples were made using these different film thicknesses. The films were first heated by a heat gun (Karl Leister, CH 6056—Hotwind S) set at 600° C. at a distance of about 6-8 inches from the nozzle. The films were then drawn around the stopper in the presence of the heat (thereby using the stopper as a male plug or mold). Care was taken to ensure that the film was adequately heated so that it would readily form without distorting the stopper shape and the heat of the heat gun did not deform the stopper. The four densified ePTFE wrapped stoppers were installed into the silicone free plastic syringe barrels for subsequent testing.

The table below demonstrates the performance as measured by the breaking and sliding friction test and the air leak test of each wrapped stopper compared to a silicone oil control. It can be seen that the thin densified ePTFE films showed better performance than the relatively thicker films with respect to providing an airtight seal. This was in part due to unavoidable wrinkling around the stopper contours in this process.

TABLE 2 P, min Syringe P break, P slide, air leak Type Film Cover (psi) (psi) (psi) (1 mL) Example 1A 14 psi 12 psi 1 psi 1 mil Densified EPTFE Example 16 14 psi 13 psi 10 psi 0.4 mil Densified EPTFE Example 1C  9 psi  8 psi 13-15 psi 0.2 mil Densified EPTFE None/Silicone  7 psi  6 psi 16-18 psi Oil BD (3 mL) Example 1A  8 psi  6 psi 1 psi 1 mil Densified EPTFE Example 1B 5-6 psi  3 psi 1 psi 0.4 mil Densified EPTFE Example 1C  5 psi 3-4 psi 7 psi 0.2 mil Densified EPTFE None/Silicone 4-5 psi 2-3 psi >20 psi Oil

Other embodiments of the present invention were constructed using a process of thermoforming a barrier preform and molding an elastomer material within the form to construct a syringe stopper.

Example 2

A barrier was created from a single densified ePTFE film 1.7-1.8 mil thick, which was obtained by the process described in U.S. Pat. No. 7,521,010 to Kennedy, et al. The film (104) was placed in the thermoforming equipment as depicted in FIG. 1 using the mold depicted in FIG. 2. The thermoforming equipment (100) uses hot air to heat the mold (200), and the pressure drop through the apparatus supplies the force to form the material. The mold has round cavities (202 a-d) having different dimensions. One of 0.380 inches, one of 0.372 inches, one of 0.365 inches, and one of 0.358 inches. The bottom portion of the cavities have a rounded corner (203) with a radius of 0.079 inches, a side straight wall 205 of 0.188 inch height, and contain a 0.201 inch wide, 2 micron porous stainless steel disc (204) at its bottom most point.

At room temperature a pressure of 5 psi was applied. The heater on the hot air system (102) (Osram Sylvania 6000 W, 240V, 25 A) was activated using a setpoint of 385° C. as measured by the thermocouple (106) above the mold. Once a temperature of 360° C. was reached below the mold cavities, as measured by the bottom thermocouple (108), the system was held for 5 minutes. Pressure was then increased by increasing the inlet air flow using the hot air system inlet valve (110). The pressure was increased at a rate of approximately 3 psi/minute from 5 psi to 13 psi. Above 13 psi, the pressure was increased at approximately 1 psi/minute up to 18 psi. This pressure was sufficient to form the densified ePTFE sheet. The sample was held at this pressure for 5 minutes, and then the heater was deactivated allowing the mold and film to cool. The mold was allowed to cool to below 50° C., as measured by the bottom thermocouple, before removing the sample. Any technique suitable for heating both the material and the mold as well as adding the air pressure to form the material will suffice. For example the mold may be simply bolted together and placed in an oven or heated press with an air line to supply the pressure. Other processes known for thermoforming, bladder forming or vacuum forming may also be used.

To coat the inside of the barrier with an elastomer solution, sample cavities were filled with a 10% by weight solution of the elastomer in MEK and allowed enough time to dry so that a substantial amount of the solvent was evaporated. Each cavity was loaded with 1-1.5 grams of elastomer (Viton GF-600S from DuPont compounded with varox D8PH and Diak 7 and processed to a crumb (304) by Eagle Elastomer Inc., Cuyahoga Falls, Ohio). The mold (306) along with the above thermoformed densified ePTFE sheet was loaded into a press with both platens (300, 302) preheated to 100° C. As represented in FIG. 3, a 10 mil Aluminum sheet (312) was placed on the lower platen (302). A Kapton sheet (308) and a steel caul plate (310) were placed below the upper press platen (300) to provide uniform pressure. The sample was heated under no pressure for 45 minutes, and then compressed under a force of 8000 lbs. The platens were slowly closed and temperature based set points were used in the following press cycle:

Step 1: Close platens

Step 2: Heat for 10 minutes at 100° C.

Step 3: 5 minutes at 120° C.

Step 4: 15 minutes at 175° C.

Step 5: 1 minute at 30° C.

Step 6: Open platens

Samples were then cut from the release sheet using a razor blade, affixed to a stopper rod using an acrylic adhesive (3M Scotch-Weld Structural Adhesive DP-8005) and installed within a standard 1 cc glass syringe barrel free of silicone oil, and tested.

Example 3

A sample was prepared in a manner similar to Example 2 except that the densified ePTFE barrier was formed to shape using a faster pressure ramp rate. The procedure of Example 2 was followed except that a pressure ramp rate of approximately 3 psi/minute from 5 psi to 18 psi was chosen. This ramp rate was obtained by closing only the exit air valve (112). This molding procedure resulted in a barrier film with milky appearance, which may indicate that there was some porosity induced in the material by the speed of the forming process.

The mold cavity was then filled with elastomer, molded and attached to a syringe stopper according to the process described in Example 2. After insertion into a glass syringe barrel the sample was tested.

Example 4

A sample was prepared in a manner similar to that described in Example 2, except that one surface of the densified ePTFE barrier material was textured before it was thermoformed. One side of the densified ePTFE material was deformed using a coarse glass bead sandblaster. The sandblaster nozzle was set to 15 psi and held approximately 9 inches away from the sample, which was affixed to a cardboard backer. The sandblaster was passed 5 times over the entire surface of the sample. This process resulted in significant mechanical deformation on one side of the film which increased the apparent surface roughness.

The barrier material was placed in the mold with the roughened side up so that it would be oriented towards the elastomer. The mold cavity was then filled with elastomer, molded and attached to a syringe stopper according to the process described in Example 2. After insertion into a glass syringe barrel, the sample was tested.

Example 5

A sample was prepared similar to Example 1 except that the densified ePTFE barrier material exposed to a plasma treatment after thermoforming. The material was left in the mold and placed in a plasma vacuum chamber with a 90/10 mix of He/H₂ and an exposure time of 10 minutes. This sample was not coated with an elastomer solution before compression molding. Otherwise the procedures of Example 2 were followed.

The mold cavity was then filled with elastomer, molded and attached to a syringe stopper.

Example 6

A sample was prepared in a manner similar to Example 2, except that an ePTFE/PFA composite film was used as a barrier. The barrier was obtained in a manner similar to that described in Example 2 of WO 94/13469 to Bacino. The resulting barrier is an ePTFE material with PFA on one of its side surfaces. The barrier material was placed in the mold with the PFA side of the composite facing upwards, such that after thermoforming the PFA would be oriented towards the inside of the mold. The thermoforming process followed that of Example 2 except that the heater setpoint was 295° C. and the mold cavity setpoint was approximately 275° C. Moreover, the pressure ramp rate in the molding process was approximately 11.5 psi/min from 5 to 18 psi. The composite material was held at 18 psi for approximately 15 seconds before cooling. After the sample was removed from the mold it was inverted so that the ePTFE layer was facing inward.

Example 7

A sample was prepared in a manner similar to Example 2 except that the barrier was an ePTFE/densified ePTFE composite. The barrier was prepared according to the methods disclosed in U.S. Pat. No. 6,030,694 to Dolan. The material was oriented in the mold with the ePTFE side of the composite downward, the molded sample was inverted after thermoforming so that the ePTFE layer was facing inward. In this example the mold that was used had the same mold cavities of diameters identical to those of Example 2 (“A”=0.380 inches, “B”=0.372 inches, “C”=0.365 inches, “D”=0.358 inches.) However, each cavity was a straight cylinder of 0.252 inch height and had a stainless steel porous disc making up the bottom of the cavity.

Example 8

Another example was constructed using an ePTFE/FEP composite obtained using the procedure described in Bacino. In this example, rather than thermoforming, the film was placed over a mold cavity and formed by compression molding. A single cavity mold was used having a profile depicted in FIG. 4. The mold had a primary diameter of 0.49 inches. The barrier material was obtained using the procedure described in Bacino.

Example 9

A layer of FEP about 0.5 mils in thickness (FEP 100, DuPont) was laminated to a layer of densified expanded PTFE film [Thickness—1 mil; Tensile Strength—13.85 ksi (longitudinal), 13.9 ksi (transverse); Modulus—19.8 ksi (longitudinal), 20.7 ksi (transverse); Strain to Break—425% (longitudinal), 425% (transverse)]. The two layers were stacked on top of each other in a pin frame and heating to 380° C. in an oven for 15 minutes. A layer of porous expanded PTFE [thickness: 27.5 micrometers, matrix tensile strength: 66.8 MPa (longitudinal), 75.8 MPa (transverse), strain to break: 131% (longitudinal), 91% (transverse), bubble point: 22.6 psi] was placed on the densified ePTFE-FEP laminate such that the porous expanded PTFE layer faced the FEP layer in the laminate. These three layers were placed between two smooth metal plates, the plates were clamped to a clamping pressure of about 1 psi. The plates were then placed in an oven at 305° C. for 15 minutes. The resulting three layer composite material (densified ePTFE-FEP-porous ePTFE) was then cooled to about 40° C.

This composite material was then thermoformed using heat and vacuum to create a pre-form. The pre-form was constructed by heating the composite to a sufficiently high temperature and then drawing the composite over a male plug using differential pressure. The composite material was loaded into the thermoforming apparatus such that the densified ePTFE layer faced the plug. The composite was heated using a hot air gun (Steinel HG2310) with air exit temperature of 380° C. by placing the gun about 5 mm away from the surface of the composite. After 5 seconds, the film was subjected to a vacuum of −85 kPa. The composite was continued to be heated for another 15 seconds and cooled to about 40° C. under vacuum.

The resulting pre-form sample was then inverted and then placed into a rubber molding cavity charged with 3.5 grams of elastomer (50 Durometer halobutyl rubber), and the stopper was formed by compression molding. The mold was built to geometry specified for 1 mL standard plunger per the ISO standard ISO11040-5:2001(E), with an additional 5% shrinkage factor incorporated.

The cavity was loaded in a press with both platens preheated to 120° C. The platens were closed to 55,500 lbs (about 8700 psi total internal pressure). The platens were then heated at 180° C. for 5 minutes and then cooled under pressure to 40° C. The pressure was released and the stopper was ejected. The resulting stopper was washed using a detergent and triple rinsed with de-ionized water. Stopper samples were then cut from the release sheet using a razor blade. They were subjected to two 30 minute cycles in an autoclave at 121° C. The static and dynamic force on the stopper was measured to be 2.5N and 2.1N respectively. The weight gain of the stopper after the Toluene Exposure test was 0 mg, indicating that the stopper functioned as an effective barrier. Further, the same stopper was subjected to the vent tube placement test and then the Toluene exposure test was repeated. The weight gain was still 0 mg, indicative of superior barrier function of the stopper. The stopper was also tested for leaks using the air leak test and no leak was detected. The areal transformation (%) was calculated to be 82%.

Example 10

A layer of EFEP about 2.7 microns thick (RP-4020, Daikin) was laminated to a layer of densified expanded PTFE film in a manner similar to the one described below. The densified expanded PTFE film had the following properties: Thickness—1 mil; Tensile Strength—13.85 ksi (longitudinal), 13.9 ksi (transverse); Modulus—19.8 ksi (longitudinal), 20.7 ksi (transverse); Strain to Break—425% (longitudinal), 425% (transverse). The two layers were stacked on top of each other in a pin frame and heated to 380° C. in an oven for 15 minutes. The resulting two-layer composite barrier (EFEP—densified expanded PTFE) was then cooled to about 40=C.

This composite barrier was then thermoformed using heat and vacuum to create a pre-form. The pre-form was constructed by heating the composite to a sufficiently high temperature to draw the composite over a male plug using differential pressure. The mold consisted of a flat plate with a 60 mm diameter woven fiberglass mat placed over an opening in the center which had a 4.8 mm recess. The male plug was a 12.7 mm diameter pin 25.4 mm in height, and was placed in the center of the mold.

The composite barrier was loaded into the thermoforming apparatus such that the densified ePTFE layer faced the plug. The composite barrier was heated using a hot air gun (Steinel HG2310) with air exit temperature of 380° C. by placing the gun about 5 mm from the surface of the composite barrier. After heating for 5 seconds, the film was subjected to a vacuum of −85 kPa. The composite barrier was heated for another 15 seconds and cooled to about 40° C. while under vacuum.

An aluminum female mold which had a cavity of a geometry to match the thermoforming pin was prepared by heating to 280° C. The mold cavity matched the geometry of the plug with 1.6 mm clearance on all sides. EFEP (RP-4020, from Daikin) resin was provided to the mold. The thermoforming pin, with the pre-form on it, was also heated to 205° C. and inserted into the mold cavity. The entire assembly was cooled to 25° C. After cooling, the molded assembly was removed, providing a container with a wall thickness of approximately 1.6 mm and a PTFE based barrier on the interior of the container. The areal transformation (%) was calculated to be 68%.

Example 11

Reference is made to FIGS. 17 a and 17 b in the following example. A layer of FEP (900) about 0.5 mils in thickness (FEP 100, DuPont) was laminated to a layer of densified expanded PTFE (920) in a manner similar to the one described below. The densified expanded PTFE film had the following properties: Thickness—1 mil; Tensile Strength—13.85 ksi (longitudinal), 13.9 ksi (transverse); Modulus—19.8 ksi (longitudinal), 20.7 ksi (transverse); Strain to Break—425% (longitudinal), 425% (transverse). The two layers were stacked on top of each other in a pin frame and heated to 380° C. in an oven for 15 minutes.

Next, a layer of porous expanded PTFE (940) was placed on the densified ePTFE-FEP laminate such that the porous expanded PTFE layer faced the FEP layer in the laminate. The porous expanded PTFE membrane had the following properties: Thickness—27.5 micrometers; Matrix Tensile Strength—66.8 MPa (longitudinal), 75.8 MPa (transverse); Strain to Break—131% (longitudinal), 91% (transverse); Bubble Point—22.6 psi. These three layers were placed between two smooth metal plates, the plates were clamped to a clamping pressure of about 1 psi. The plates were then placed in an oven at 305° C. for 15 minutes. The resulting three-layer composite material was then cooled to about 40° C.

The three-layer composite material was then thermoformed in combination with an additional layer (960) of 10 mil thick Kynar® 2800 PVDF, hand laid in contact with the porous ePTFE side of the composite. Heat and vacuum were used to create a pre-form. The pre-form was constructed by heating the composite to a sufficiently high temperature to draw the composite over a male plug mold using differential pressure. The three-layer composite material with the additional PVDF layer was loaded into the thermoforming apparatus such that the densified ePTFE (920) layer faced the plug. The mold consisted of a 60 mm sintered stainless steel plate with a 8.3 mm lip on the outer edge and the plug located in the center. The plug was made of stainless steel and had a diameter of 15.9 mm and a height of 15.9 mm.

The composite with the additional PVDF layer was heated using a hot air gun (Steinel HG2310) with air exit temperature of 380° C. by placing the gun about 5 mm away from the surface of the composite. After heating for 5 seconds, the film was subjected to a vacuum of −85 kPa. The composite with the additional PVDF layer was heated for another 15 seconds and cooled to about 40° C. while under vacuum.

The resulting article (980) was shaped in the form of a container and shown in FIG. 17. The areal transformation (%) was calculated to be 118%.

Comparative Example A

Commercial siliconized butyl stopper made for 1 cc single dose glass prefilled syringe.

TABLE 3 Static Dynamic Leak Force Force pressure Sample Material Cavity (grams) (grams) (kPa) Example 2 Densified A 1517.2 1232.7 Pass ePTFE C 583.5 558.1 Pass D 358.4 287.1 −88 Example 3 Low porosity A 1528.4 1511.2 Pass ePTFE B 915.3 880.9 Pass C 621.8 735.6 Pass D 418.6 418.5 −88 Example 4 Mechanically A 979.7 777.5 Pass deformed B 734.1 612.3 Pass densified C 705.5 655.5 Pass ePTFE D 665.9 478.6 Pass B 1769.2 1635.4 Pass C 844.0 638.5 Pass D 574.6 415.3 −88 Example 6 ePTFE/PFA A 2683.8 1991.0 Pass composite B 2244.4 1790.8 Pass C 1675.3 1291.0 Pass Comparative Butyl + n/a 750.5 323.7 Pass Example A silicone oil

The invention of this application has been described above both generically and with regard to specific embodiments. It will be apparent to those skilled in the art that various modifications and variations can be made in the embodiments without departing from the scope of the disclosure. Thus, it is intended that the embodiments cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents. 

1. A molded article comprising: a. a support; and b. a composite barrier adjacent to the support, the composite barrier comprising: a densified expanded fluoropolymer layer; and a tie layer comprising a non-fluoropolymer material, said tie layer being positioned between said support and said densified expanded fluoropolymer layer.
 2. The molded article of claim 1, wherein said non-fluoropolymer material is selected from the group consisting of non-fluoropolymer membranes, non-fluoropolymer microporous membranes, spunbonded materials, melt blown fibrous materials, electrospun nanofibers, polyvinylidene difluoride (PVDF), nanofibers, polysulfones, polyethersulfones, polyarlysolfones, polyether ether ketone (PEEK), polyethylenes, polypropylenes and polyimides.
 3. The molded article of claim 2, wherein said non-fluoropolymer material is selected from the group consisting of polyvinylidene difluoride (PVDF), nanofibers, polysulfones, polyethersulfones, polyarlysolfones, polyether ether ketone (PEEK), polyethylenes, polypropylenes and polyimides.
 4. The molded article of claim 1, wherein said densified expanded fluoropolymer layer is expanded polytetrafluoroethylene (ePTFE).
 5. The molded article of claim 1, wherein said tie layer is at least partially porous.
 6. The molded article of claim 1, wherein said densified expanded fluoropolymer layer comprises a copolymer of at least 50 mol % tetrafluoroethylene (TFE).
 7. The molded article of claim 1, wherein said support is selected from the group consisting of butyl rubber, bromobutyl rubber, chlorobutyl rubber, silicone, nitrile, styrene butadiene, polychloroprene, ethylene propylene diene, fluoroelastomers and combinations thereof.
 8. A syringe stopper comprising: an elastomer body; a non-fluoropolymer tie layer adjacent said elastomer body; and a barrier film comprising an expanded fluoropolymer adjacent said non-fluoropolymer tie layer.
 9. The syringe stopper of claim 8, wherein said non-fluoropolymer tie layer comprises at least one member selected from the group consisting of non-fluoropolymer material is selected from the group consisting of non-fluoropolymer membranes, non-fluoropolymer microporous membranes, spunbonded materials, melt blown fibrous materials, electrospun nanofibers, polyvinylidene difluoride (PVDF), nanofibers, polysulfones, polyethersulfones, polyarlysolfones, polyether ether ketone (PEEK), polyethylenes, polypropylenes and polyimides.
 10. The syringe stopper of claim 9, wherein said non-fluoropolymer tie layer comprises at least one member selected from the group consisting of polyvinylidene difluoride (PVDF), nanofibers, polysulfones, polyethersulfones, polyarlysolfones, polyether ether ketone (PEEK), polyethylenes, polypropylenes and polyimides.
 11. The syringe stopper of claim 8, wherein said barrier film has a thickness of less than 15 microns.
 12. The syringe stopper of claim 8, wherein said barrier film is expanded polytetrafluoroethylene.
 13. The syringe stopper of claim 8, wherein said barrier film is bonded to said elastomer body and said non-fluoropolymer tie layer is bonded to said expanded fluoropolymer film.
 14. The syringe stopper of claim 8, wherein said elastomer body is selected from the group consisting of butyl rubber, bromobutyl rubber, chlorobutyl rubber, silicone, nitrile, styrene butadiene, polychloroprene, ethylene propylene diene, fluoroelastomers and combinations thereof.
 15. A syringe stopper comprising: a) an elastomeric body, b) a composite layer having a first side comprising a tie layer and a second side comprising a thermoplastic fluoropolymer, and c) a densified expanded polytetrafluoroethylene (ePTFE) film, wherein the first side of the composite layer is bonded to the elastomeric body and the second side of the composite is bonded to the fluoropolymer film.
 16. The syringe stopper of claim 15, wherein said non-fluoropolymer tie layer comprises at least one member selected from the group consisting of non-fluoropolymer material is selected from the group consisting of non-fluoropolymer membranes, non-fluoropolymer microporous membranes, spunbonded materials, melt blown fibrous materials, electrospun nanofibers, polyvinylidene difluoride (PVDF), nanofibers, polysulfones, polyethersulfones, polyarlysolfones, polyether ether ketone (PEEK), polyethylenes, polypropylenes and polyimides.
 17. The syringe stopper of claim 15, wherein said non-fluoropolymer tie layer comprises at least one member selected from the group consisting of polyvinylidene difluoride (PVDF), nanofibers, polysulfones, polyethersulfones, polyarlysolfones, polyether ether ketone (PEEK), polyethylenes, polypropylenes and polyimides.
 18. The syringe stopper of claim 15, wherein said barrier film has a thickness of less than 15 microns.
 19. The syringe stopper of claim 15, wherein said elastomeric body is selected from the group consisting of butyl rubber, bromobutyl rubber, chlorobutyl rubber, silicone, nitrile, styrene butadiene, polychloroprene, ethylene propylene diene, fluoroelastomers and combinations thereof. 